[unreadable] [unreadable] Choline and betaine are nutrients involved in methyl-group metabolism, which is critical for DNA synthesis and methylation. Choline is also a precursor of membrane phospholipids, phosphatidylcholine and sphingomyelin. Animal studies have demonstrated that choline deficiency is a condition sufficient for the development of hepatocellular carcinoma in the absence of other carcinogens. A methyl-group-deficient diet with no choline and low methionine promotes chemically induced carcinogenesis in animals. Dietary factors related to methyl- group metabolism, including folate, alcohol, and methionine have been associated with cancers of several organs in human. However, the relation between choline and betaine intake and human cancers is unknown. Some animal studies have shown that repletion of choline following choline deficiency actually promote carcinogenesis. Thus, the association between choline and cancer may be more complicated and may involve other mechanisms other than methyl-group metabolism. Understanding the role of choline and betaine in human health has been hampered by lack of food composition data. Recently, we obtained choline and betaine composition data for foods measured by our food frequency questionnaire and found that higher choline and betaine intake was associated with lower fasting plasma homocysteine levels in women and men and higher choline intake was associated with an elevated risk of colorectal adenoma in women. In this proposed work, we would like to further expand our knowledge on the biological role of dietary choline and betaine in methyl-group metabolism and colonic carcinogenesis. First, using data from the Framingham Offspring Study, we propose to examine the relation between choline and betaine intake and plasma levels of postmethionine-loading homocysteine, an intermediate product in methyl-group metabolism and a potential indicator of body's methyl-group availability. Evaluation of postmethionine-loading levels rather than fasting levels of homocysteine will provide useful data, simulating biological conditions after a meal. We expect to include a total of 2,732 participants with diet and blood data. Second, we will examine choline and betaine intake in relation to the risks of colorectal adenoma and colorectal cancer in the Health Professionals Follow-up Study, a large prospective study of men. We expect to have 4,143 adenoma and 1,305 cancer cases. We will take advantage of existing high-quality and large size datasets. Because we attained experience and knowledge in choline research from our previous grant, we will be able to carry out the proposed work in an extremely time- and cost-effective manner. The findings from the proposed grant will complement our previous work on choline and betaine and enhance our understanding of the role of these nutrients in carcinogenesis in human as this area of research is largely unexplored. [unreadable] [unreadable] [unreadable]